Synthesis of heterocyclic compounds

ABSTRACT

Provided herein are intermediates and processes useful for facile synthesis of compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein Q, P 1  and P 2  are as defined in this disclosure.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/161,103, filed May 20, 2016, which claims the benefit under 35 U.S.C.§119(e) to U.S. Provisional Application No. 62/165,808, filed May 22,2015, which is hereby incorporated by reference in its entirety.

FIELD

The present disclosure relates to heterocyclic compounds, methods forthe preparation thereof, and compounds prepared employing same.

BACKGROUND

(R)-N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamideis a potent inhibitor of mutated forms of B-raf B, and can be useful fortreatment of B-raf mediated diseases, such as metastatic melanoma,thyroid cancers and colorectal cancers. The compound and its synthesishave been described in WO 2012/109075. There remains interest indeveloping other versatile and facile processes for the efficientpreparation of this and other biologically active molecules, especially,on an industrial scale.

SUMMARY

In one embodiment, the present disclosure provides a compound of formula(I):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomeror a deuterated analog thereof, wherein:

Q is F or H;

P¹ is

R¹ is H or halogen;

n is 0, 1 or 2;

m is 1 or 2;

P² is —C(O)—R³ or —C(O)—OR⁴;

R³ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 substituents as described inthis disclosure; and

R⁴ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 substituents as described inthis disclosure.

In another embodiment, the present disclosure provides a method forpreparing a compound of formula (Ia):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomeror a deuterated analog thereof, said method comprising:

contacting a compound of formula (II):

with an agent of the formula:

under conditions sufficient to form the compound of formula (Ia),wherein:

X¹ is Sn(Bu)₃ or B(OR⁵)₂;

L¹ is Br, Cl, I, tosyl-O—, mesyl-O—, trifluoromethanesulfonyl-O—,—C(O)—O—CF₃ or —C(O)—O—CH₃C(O)O—;

Q is F or H;

P² is —C(O)—R³ or —C(O)—OR⁴;

R³ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀-cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 substituents as described inthis disclosure;

R⁴ is C¹⁻⁶alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 substituents as described inthis disclosure; and

R⁵ is H or C₁₋₆alkyl which can be optionally substituted with halogen,—OH, or —CN.

In yet another embodiment, the present disclosure provides a method forpreparing a compound of formula (I):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomeror a deuterated analog, thereof, said method comprising:

contacting a compound of formula (Ia) with L²-P¹under conditionssufficient to form the compound of formula (I), wherein:

P¹ is 9-fluorenylmethoxycarbonyl, t-butoxycarbonyl, trimethylsilyl,t-butyldiphenylsilyl,

P² is —C(O)—R³ or —C(O)—OR⁴;

R¹ is H or halogen;

R³ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 substituents as described inthis disclosure;

R⁴ is C₃₋₁₀alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl,heteroaryl-C₁₋₂alkyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl,ethynyl or vinyl, each of which is optionally substituted with 1-3substituents as described in this disclosure;

Q is H or F;

L¹ is Br, Cl, I, —OSO₂—R¹ or —C(O)—O—R²; wherein R¹ and R² are eachindependently optionally substituted aryl or optionally substitutedC₁₋₆alkyl;

L² is Br, Cl, I, tosyl-O—, mesyl-O—, trifluoromethanesulfonyl-O—,—C(O)—O—CF₃ or —C(O)—O—CH₃;

m is 1 or 2; and

n is 1 or 2.

In yet another embodiment, the present disclosure provides a method forpreparing a compound of formula (III):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomeror a deuterated analog thereof, said method comprising:

(1) reacting a compound of formula (Ib):

under conditions sufficient to N-deprotect formula (I) and form thecompound of formula (III),

wherein:

Z is

R¹ is flouro or chloro;

Q is H or fluoro;

n is 0, 1 or 2;

m is 1 or 2;

P² is —C(O)—R³ or —C(O)—OR⁴;

R³ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 substituents as described inthis disclosure; and

R⁴ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 substituents as described inthis disclosure.

DETAILED DESCRIPTION

The present disclosure is related to novel synthetic intermediates andprocesses for the large-scale preparation of compounds that have thefollowing core structure:

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomeror a deuterated analog thereof, wherein:

Z is

Q is fluoro or chloro;

R₁ is fluoro or chloro;

m is 1 or 2; and

n is 1 or 2.

The wavy lines indicate the points of attachment to the remainder of thestructure. For example, the present disclosure provides syntheticmethods and intermediates useful for the large scale preparation of(R)-N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamidehaving the following structure:

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomeror a deuterated analog thereof.

Advantageously, the present disclosure provides synthetic intermediatesand versatile processes, which allow for high efficiency, low cost andlarge-scale facile synthesis of biologically active molecules with highpurity. The intermediates of the present disclosure can be readilyadapted to the facile preparation of various compounds having a fluorosubstituent.

Definitions

It is noted here that as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referenceunless the context clearly dictates otherwise.

“Halogen” or “halo” refers to all halogens, that is, chloro (Cl), fluoro(F), bromo (Br), or iodo (I).

“Hydroxyl” or “hydroxy” refers to the group —OH.

“Thiol” refers to the group —SH.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbon,having the number of carbon atoms designated (i.e. C₁₋₆ means one to sixcarbons). Representative alkyl groups include straight and branchedchain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbonatoms. Further representative alkyl groups include straight and branchedchain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl,n-octyl, and the like. For each of the definitions herein (e.g., alkyl,alkoxy, alkylamino, alkylthio, alkylene, haloalkyl, arylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl), when a prefixis not included to indicate the number of carbon atoms in an alkylportion, the alkyl moiety or portion thereof will have 12 or fewer mainchain carbon atoms or 8 or fewer main chain carbon atoms or 6 or fewermain chain carbon atoms. For example, C₁₋₈ alkyl refers to a straight orbranched hydrocarbon having 1, 2, 3, 4, 5 or 6 carbon atoms andincludes, but are not limited to, C₁₋₂ alkyl, C₁₋₄ alkyl, C₂₋₆ alkyl,C₂₋₄ alkyl, C₁₋₆ alkyl, C₂₋₈ alkyl, C₁₋₇ alkyl, C₂₋₇ alkyl and C₃₋₆alkyl. “Fluoro substituted alkyl” denotes an alkyl group substitutedwith one or more fluoro atoms, such as perfluoroalkyl, where preferablythe lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also1, 2, or 3 fluoro atoms. While it is understood that substitutions areattached at any available atom to produce a stable compound, whenoptionally substituted alkyl is an R group of a moiety such as —OR (e.g.alkoxy), -SR (e.g. thioalkyl), —NHR (e.g. alkylamino), —C(O)NHR, and thelike, substitution of the alkyl R group is such that substitution of thealkyl carbon bound to any O, S, or N of the moiety (except where N is aheteroaryl ring atom) excludes substituents that would result in any O,S, or N of the substituent (except where N is a heteroaryl ring atom)being bound to the alkyl carbon bound to any O, S, or N of the moiety.

The term “alkylene” by itself or as part of another substituent means alinear or branched saturated divalent hydrocarbon moiety derived from analkane having the number of carbon atoms indicated in the prefix. Forexample, (i.e., C₁₋₆ means one to six carbons; C₁₋₆ alkylene is meant toinclude methylene, ethylene, propylene, 2-methylpropylene, pentylene,hexylene and the like). C₁₋₄ alkylene includes methylene —CH₂—, ethylene—CH₂CH₂—, propylene —CH₂CH₂CH₂—, and isopropylene —CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —CH₂—(CH₂)₂CH₂—, —CH₂—CH(CH₃)CH₂—, —CH₂—C(CH₃)₂—,—CH₂—CH₂CH(CH₃)—. Typically, an alkyl (or alkylene) group will have from1 to 24 carbon atoms, with those groups having 10 or fewer, 8 or fewer,or 6 or fewer carbon atoms being preferred in the present disclosure.When a prefix is not included to indicate the number of carbon atoms inan alkylene portion, the alkylene moiety or portion thereof will have 12or fewer main chain carbon atoms or 8 or fewer main chain carbon atoms,6 or fewer main chain carbon atoms or 4 or fewer main chain carbonatoms.

“Cycloalkylalkyl” refers to an -(alkylene)-cycloalkyl group wherealkylene as defined herein has the indicated number of carbon atoms orif unspecified having six or fewer, preferably four or fewer main chaincarbon atoms; and cycloalkyl is as defined herein has the indicatednumber of carbon atoms. C₃₋₈cycloalkyl-C₁₋₂alkyl meansC₃₋₈cycloalkyl-C₁₋₂alkylene, wherein the cycloalkyl has 3 to 8 ringcarbon atoms and the alkylene has 1 or 2 carbon atoms. Exemplarycycloalkylalkyl include, e.g., cyclopropylmethylene, cyclobutylethylene,cyclobutylmethylene, and the like.

“Cycloalkyl” by itself or as part of another substituent, refers tosaturated or unsaturated, non-aromatic monocyclic, bicyclic or tricycliccarbon ring systems of 3-10, also 3-8, more preferably 3-6, ring membersper ring, such as cyclopropyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl,adamantyl, and the like. Cycloalkyl refers to hydrocarbon rings havingthe indicated number of ring atoms (e.g., C3-8 cycloalkyl means three toeight ring carbon atoms).

“Haloalkyl” is meant to include alkyl substituted by one to sevenhalogen atoms. Haloalkyl includes monohaloalkyl and polyhaloalkyl. Forexample, the term “C1-6 haloalkyl” is meant to include trifluoromethyl,difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

“Haloalkoxy” refers to a —O-haloalkyl group, where haloalkyl is asdefined herein, e. g., trifluoromethoxy, 2,2,2-trifluoroethoxy,difluoromethoxy, and the like.

“Alkoxy” refers to a —O-alkyl group, where alkyl is as defined herein.“Cycloalkoxy” refers to a —O-cycloalkyl group, where cycloalkyl is asdefined herein. “Fluoro substituted alkoxy” denotes alkoxy in which thealkyl is substituted with one or more fluoro atoms, where preferably thealkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3fluoro atoms. While it is understood that substitutions on alkoxy areattached at any available atom to produce a stable compound,substitution of alkoxy is such that O, S, or N (except where N is aheteroaryl ring atom), are not bound to the alkyl carbon bound to thealkoxy O. Further, where alkoxy is described as a substituent of anothermoiety, the alkoxy oxygen is not bound to a carbon atom that is bound toan O, S, or N of the other moiety (except where N is a heteroaryl ringatom), or to an alkene or alkyne carbon of the other moiety.

“Amino” or “amine” denotes the group —NH2.

“Alkylamino” refers to a —NH-alkyl group, where alkyl is as definedherein. Exemplary alkylamino groups include CH3NH—, ethylamino, and thelike.

“Dialkylamino” refers to a —N(alkyl)(alkyl) group, where each alkyl isindependently as defined herein. Exemplary dialkylamino groups includedimethylamino, diethylamino, ethylmethylamino, and the like.

“Cycloalkylamino” denotes the group —NRddRee, where Rdd and Ree combinewith the nitrogen to form a 5-7 membered heterocycloalkyl ring, wherethe heterocycloalkyl may contain an additional heteroatom within thering, such as O, N, or S, and may also be further substituted withalkyl, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, arylalkyl,heteroarylalkyl, cycloalkyl, cycloalkylalkyl or R′ as defined herein.Alternatively, “cycloalkylamino” refers to a —NH-cycloalkyl group, wherecycloalkyl is as defined herein.

“Arylamino” refers to a —NH-aryl group, where aryl is as defined herein.Exemplary arylamino groups include PhNH—, naphthylamino, and the like.

“Heteroarylamino” refers to a —NH-heteroaryl group, where heteroaryl isas defined herein. Exemplary heteroarylamino groups includepyridinyl-NH—, pyrimidinyl-amino, and the like.

“Aryl” by itself or as part of another substituent refers to amonocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbonmoiety containing 6 to 14 ring carbon atoms. Non-limiting examples ofunsubstituted aryl groups include phenyl, 1-naphthyl, 2-naphthyl and4-biphenyl. Exemplary aryl group, such as phenyl or naphthyl, which maybe optionally fused with a cycloalkyl of preferably 5-7, more preferably5-6, ring members.

“Arylalkyl” refers to -(alkylene)-aryl, where the alkylene group is asdefined herein and has the indicated number of carbon atoms, or ifunspecified having six or fewer main chain carbon atoms or four or fewermain chain carbon atoms; and aryl is as defined herein. For example,aryl-C₁₋₂alkyl means aryl-alkylene-, where the alkylene has 1 or 2carbon atoms. Examples of arylalkyl include benzyl, phenethyl, and thelike.

“Heteroaryl” by itself or as part of another substituent refers to amonocyclic aromatic ring structure containing 5 or 6 ring atoms, or abicyclic aromatic group having 8 to 10 atoms, containing one or more,preferably 1-4, more preferably 1-3, even more preferably 1-2,heteroatoms independently selected from the group consisting of O, S,and N. Heteroaryl is also intended to include oxidized S or N, such assulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon ornitrogen atom is the point of attachment of the heteroaryl ringstructure such that a stable compound is produced. Examples ofheteroaryl groups include, but are not limited to, pyridinyl,pyridazinyl, pyrazinyl, indolizinyl, benzo[b]thienyl, quinazolinyl,purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl,oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl,tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, indolyl,triazinyl, quinoxalinyl, cinnolinyl, phthalaziniyl, benzotriazinyl,benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl,isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl,thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines,benzothiaxolyl, benzothienyl, quinolyl, isoquinolyl, indazolyl,pteridinyl and thiadiazolyl. “Nitrogen containing heteroaryl” refers toheteroaryl wherein any heteroatoms are N.

“Heteroarylalkyl” refers to -(alkylene)-heteroaryl, where the alkylenegroup is as defined herein and has the indicated number of carbon atoms,or if unspecified having six or fewer main chain carbon atoms or four orfewer main chain carbon atoms; and heteroaryl is as defined herein. Forexample, heteroaryl-C1-2alkyl means heteroaryl-alkylene-, where thealkylene has 1 or 2 carbon atoms. Examples of heteroarylalkyl include2-pyridylmethyl, 2-thiazolylethyl, and the like.

“Heterocycloalkyl” refers to a saturated or unsaturated non-aromaticcycloalkyl group that contains from one to five heteroatoms selectedfrom N, O, and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized, theremaining ring atoms being C, where one or two C atoms may optionally bereplaced by a carbonyl. The heterocycloalkyl may be a monocyclic, abicyclic or a polycylic ring system of 3 to 12, preferably 4 to 10 ringatoms, more preferably 5 to 8 ring atoms, even more preferably 4-6 ringatoms in which one to five ring atoms are heteroatoms selected from —N═,—N—, —O—, —S—, —S(O)—, or —S(O)₂— and further wherein one or two ringatoms are optionally replaced by a —C(O)— group. The heterocycloalkylcan also be a heterocyclic alkyl ring fused with a cycloalkyl, an arylor a heteroaryl ring. Non limiting examples of heterocycloalkyl groupsinclude pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl,butyrolactam moiety, valerolactam moiety, imidazolidinone moiety,hydantoin, dioxolane moiety, phthalimide moiety, piperidine, 1,4-dioxanemoiety, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide,thiomorpholinyl-S,S-oxide, piperazinyl, pyranyl, pyridine moiety,3-pyrrolinyl, thiopyranyl, pyrone moiety, tetrahydrofuranyl,tetrahydrothiophenyl, quinuclidinyl, and the like. A heterocycloalkylgroup can be attached to the remainder of the molecule through a ringcarbon or a heteroatom.

“Heterocycloalkylalkyl” refers to -(alkylene)-heterocycloalkyl, wherethe alkylene group is as defined herein and has the indicated number ofcarbon atoms, or if unspecified having six or fewer main chain carbonatoms or four or fewer main chain carbon atoms; and heterocycloalkyl isas defined herein. Examples of heterocycloalkylalkyl include2-pyridylmethyl, 2-thiazolylethyl, and the like.

The substituents for alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl,cycloalkylalkyl, alkylene, vinyl include, but are not limited to, R′,halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂,—S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OR′, —SR′,—OC(O)R′, —OC(S)R′, —C(O)R′, —C(S)R′, —C(O)OR′, —C(S)OR′, —S(O)R′,—S(O)₂R′, —C(O)NHR′, —C(S)NHR′, —C(O)NR′R″, —C(S)NR′R″, —S(O)₂NHR′,—S(O)₂NR′R″, —C(NH)NHR′, —C(NH)NR′R″, —NHC(O)R′, —NHC(S)R′, —NR″C(O)R′,—NR′C(S)R″, —NHS(O)₂R′, —NR′S(O)₂R″, —NHC(O)NHR′, —NHC(S)NHR′,—NR′C(O)NH₂, —NR′C(S)NH₂, —NR′C(O)NHR″, —NR′C(S)NHR″, —NHC(O)NR′R″,—NHC(S)NR′R″, —NR′C(O)NR″R′″, —NR′″C(S)NR′R″, —NHS(O)₂NHR′,—NR′S(O)₂NH₂, —NR′S(O)₂NHR″, —NHS(O)₂NR′R″, —NR′S(O)₂NR″R′″, —NHR′, and—NR′R″ in a number ranging from zero to (2m′+1), where m′ is the totalnumber of carbon atoms in such group. R′, R″ and R′″ each independentlyrefer to hydrogen, C₁₋₈ alkyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, aryl substituted with 1-3 halogens, C₁₋₈alkoxy, haloalkyl, haloalkoxy or C₁₋₈ thioalkoxy groups, orunsubstituted aryl-C₁₋₄ alkyl groups. When R′ and R″ are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 3-, 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant toinclude 1-pyrrolidinyl and 4-morpholinyl. R′, R″ and R′″ can be furthersubstituted with Ra^(a1), halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH,—C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂, —NH(S)O₂NH₂, —C(NH)NH₂, —OR^(a1), —SR^(a1), —OC(O)R^(a1), —OC(S)R^(a1),—C(O)R^(a1), —C(S)R^(a1), —C(O)OR^(a1), —C(S)OR^(a1), —S(O)R^(a1),—S(O)₂R^(a1), —C(O)NHR^(a1), —C(S)NHR^(a1), —C(O)NR^(a1)R^(a2),—C(S)NR^(a1)R^(a2), —S(O)₂NHR^(a1), —S(O)₂NR^(a1)R^(a2), —C(NH)NHR^(a1),—C(NH)NR^(a1)R^(a2), —NHC(O)R^(a1), —NHC(S)R^(al), —NR^(a2)C(O)R^(a1),—NR^(a1)C(S)R^(a2), NHS(O)₂R^(a1), —NR^(a1)S(O)₂R^(a2), —NHC(O)NHR^(a1),—NHC(S)NHR^(a1), —NR^(a1)C(O) NH₂, —NR^(a1)C(S)NH₂,—NR^(a1)C(O)NHR^(a2), —NR^(a1)C(S)NHR^(a2), —NHC(O)NR^(a1)R^(a2),—NHC(S)NR^(a1)R^(a2), —NR^(a1)C(O)NR^(a2)R^(a3),—NR^(a3)C(S)NR^(al)R^(a2), —NHS(O)₂NHR^(a1), —NR^(a1)S(O)₂NH₂,—NR^(al)S(O)₂NHR^(a2), —NHS(O)₂NR^(a1)R^(a1)R^(a2),—NR^(a1)S(O)₂NR^(a2)R^(a3) , —NHR^(a1), and —NR^(a1)R^(a2) in a numberranging from zero to (2n′+1), where n′ is the total number of carbonatoms in such group. R^(a1), R^(a2) and R^(a3) each independently referto hydrogen, C₁₋₈ alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, aryl substituted with 1-3 halogens, C₁₋₈ alkoxy,haloalkyl, haloalkoxy or C₁₋₈ thioalkoxy groups, or unsubstitutedaryl-C₁₋₆alkyl groups. R^(a1), R^(a2) and R^(a3) can be furthersubstituted with R^(b1), halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH,—C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR^(bl), —SR^(b1), —OC(O)R^(b1), —OC(S)R^(b1),—C(O)R^(b1), —C(S)R^(b1), —C(O)OR^(b1), —C(S)OR^(b1), —S(O)R^(b1),—S(O)₂R^(b1), —C(O)NHR^(b1), —C(S)NHR^(b1), —C(O)NR^(b1)R^(b2),—C(S)NR^(b1)R^(b2), —S(O)₂NHR^(b1), —S(O)₂NR^(b1)R^(b2), —C(NH)NHR^(b1),—C(NH)NR^(b1)R^(b2), —NHC(O)R^(b1), —NHC(S)R^(b1), —NR^(b2)C(O)R^(b1),—NR^(b1)C(S)R^(b2), —NHS(O)₂R^(b1), —NR^(b1)S(O)₂R^(b2),—NHC(O)NHR^(b1)R^(b2), —NHC(S)NHR^(b1), —NR^(b1)C(O)NH₂,—NR^(b1)C(S)NH₂, —NR^(b1)C(O)NHR^(b2), —NR^(b1)C(S)NHR^(b2),—NHC(O)NR^(b1)R^(b1), R^(b2), —NHC(S)NR^(b1)R^(b2),—NR^(b1)C(O)NR^(b2)R^(b3), —NR^(b3)C(S)NR^(b1)R^(b2), —NHS(O)₂NHR^(b1),—NR^(b1)S(O)₂NH₂, —NR^(b1)S(O)₂NHRb^(b2), —NHS(O)₂NR^(b1)R^(b2),—NR^(b1)S(O)₂NR^(b2)R^(b3), —NHR^(b1), and —NR^(b1)R^(b2) in a numberranging from zero to (2p′+1), where p′ is the total number of carbonatoms in such group. R^(b1), R^(b2) and R^(b3) each independently referto hydrogen, C₁₋₈ alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, aryl substituted with 1-3 halogens, C₁₋₈ alkoxy,haloalkyl, haloalkoxy or C₁₋₈ thioalkoxy groups, or unsubstitutedaryl-C₁₋₄ alkyl groups.

Substituents for the aryl and heteroaryl groups are varied and aregenerally selected from: R′, halogen, —OH, —NH₂, —NO₂, —CN, —C(O)OH,—C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR′, —SR′, —OC(O)R′, —OC(S)R′, —C(O)R′,—C(S)R′, —C(O)OR′, —C(S)OR′, —S(O)R′, —S(O)₂R′, —C(O)NHR′, 13 C(S)NHR′,—C(O)NR′R″, —C(S)NR′R″, —S(O)₂NHR′, —S(O)₂NR′R″, —C(NH)NHR′,—C(NH)NR′R″, —NHC(O)R′, —NHC(S)R′, —NR″C(O)R′, —NR′C(S)R″, —NHS(O)₂R′,—NR′S(O)₂R″, —NHC(O)NHR′, —NHC(S)NHR′, —NR′C(O)NH₂, —NR′C(S)NH₂,—NR′C(O)NHR″, —NR′C(S)NHR″, —NHC(O)NR′R″, —NHC (S)NR′R″, —NR′C(O)NR ″R″,—NR′″C(S)NR′R″, —NHS(O)₂NHR′, —NR′S(O)₂NH₂, —NR′S(O)₂NH R″,—NHS(O)₂NR′R″, —NR′S(O)₂NR″R′″, —NHR′, —NR′R″, —N₃,perfluoro(C₁₋₄)alkoxy, and perfluoro(C₁₋₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R″′ are independently selected fromhydrogen, haloalkyl, haloalkoxy, C₁₋₈ alkyl, C₃₋₆ cycloalkyl,cycloalkylalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, aryl-C₁₋₄ alkyl, and aryloxy-C₁₋₄ alkyl.Other suitable substituents include each of the above aryl substituentsattached to a ring atom by an alkylene tether of from 1-4 carbon atoms.R′, R″ and R″′ can be further substituted with R^(a1), halogen, —OH,—NH², —NO₂, —CN, —C(O)OH, —C(S)OH, —C(O)NH₂, —C(S)NH₂, —S(O)₂NH₂,—NHC(O)NH₂, —NHC(S)NH₂, —NHS(O)₂NH₂, —C(NH)NH₂, —OC(O)R^(a1), —SR^(a1),—OC(O)R^(a1), —OC(S)R^(a1), —C(O)R^(a1), —C(S)R^(a1), —C(O)OR^(a1),—C(S)OR^(a1), —S(O)R^(a1), —S(O)₂R^(a1), —C(O)NHR^(a1), —C(S)NHR^(a1),—C(O)NR^(a1)R^(a2), —C(S)NR^(a1)R^(a2), —S(O)₂NHR^(a1),—S(O)₂NR^(a1)R^(a2), —C(NH)NHR^(a1), —C(NH)NR^(a1)R^(a2), —NHC(O)R^(a1),—NHC(S)R^(a1), —NR^(a2)C(O)R^(a1), —NR^(a1)C(S)R^(a2), —NHS(O)₂R^(a1),—NR^(a1)S(O)₂R^(a2), —NHC(O)NHR^(a1), —NHC(S)NHR^(a1), —NR^(a1)C(O)NH₂,—NR^(a1)C(S)NH₂, —NR^(a1)C(O)NHR^(a2), —NR^(a1)C(S)NHR^(a2),—NHC(O)NR^(a1)R^(a2), —NHC(S)NR^(a1)R^(a2), —NR^(a1)(O)NR^(a2)R^(a3),—NR^(a3)C(S)NR^(a1)R^(a2), —NHS(O)₂NHR^(a1), —NR^(a1)S(O)₂NH₂,—NR^(a1)S(O)₂NHR^(a2), —NHS(O)₂NR^(a1)R^(a2),—NR^(a1)S(O)₂NR^(a2)R^(a3), —NHR^(a1), —NR^(a1)R^(a2), —N₃,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R^(a1), R^(a2) and R^(a3) are each independentlyselected from hydrogen, haloalkyl, haloalkoxy, C₁₋₈alkyl, C₃₋₆cycloalkyl, cycloalkylalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, aryl-C₁₋₄ alkyl, or aryloxy-C₁₋₄alkyl. Other suitable substituents include each of the above arylsubstituents attached to a ring atom by an alkylene tether of from 1-4carbon atoms.

When two substituents are present on adjacent atoms of a substitutedaryl or a substituted heteroaryl ring, such substituents may optionallybe replaced with a substituent of the formula -T-C(O)—(CH₂)_(q)—U—,wherein T and U are independently —NH—, —O—, —CH₂— or a single bond, andq is an integer of from 0 to 2. Alternatively, when two substituents arepresent on adjacent atoms of a substituted aryl or a substitutedheteroaryl ring, such substituents may optionally be replaced with asubstituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CH₂—, —O—, —NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or asingle bond, and r is an integer of from 1 to 3. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, when two substituents are present on adjacent atoms of asubstituted aryl or a substituted heteroaryl ring, such substituents mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁₋₆ alkyl.

“Protecting group” refers to a grouping of atoms that when attached to areactive group in a molecule masks, reduces or prevents that reactivity.Examples of protecting groups can be found in T. W. Greene and P. G.Wuts, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, (Wiley, 4th ed. 2006),Beaucage and Iyer, Tetrahedron 48:2223-2311 (1992), and Harrison andHarrison et al., COMPENDIUM OF SYNTHETIC ORGANIC METHODS, Vols. 1-8(John Wiley and Sons. 1971-1996). Representative amino protecting groupsinclude formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl(CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS),2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC),nitro-veratryloxycarbonyl (NVOC), tri-isopropylsilyl (TIPS),phenylsulphonyl and the like (see also, Boyle, A. L. (Editor),carbamates, amides, N-sulfonyl derivatives, groups of formula —C(O)OR,wherein R is, for example, methyl, ethyl, t-butyl, benzyl, phenylethyl,CH₂═CHCH₂—, and the like, groups of the formula —C(O)R′, wherein R′ is,for example, methyl, phenyl, trifluoromethyl, and the like, groups ofthe formula —SO₂R″, wherein R″ is, for example, tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl,2,3,6-trimethyl-4-methoxyphenyl, and the like, and silanyl containinggroups, such as 2-trimethylsilylethoxymethyl, t-butyldimethylsilyl,triisopropylsilyl, and the like, CURRENT PROTOCOLS IN NUCLEIC ACIDCHEMISTRY, John Wiley and Sons, New York, Volume 1, 2000).

The term “Labile protecting group” refers to those protecting groupsthat are removable under mild conditions that do not significantlyimpact other protecting groups or the remainder of the molecule.

The term “Leaving group” has the meaning conventionally associated withit in synthetic organic chemistry, i.e., an atom or a group capable ofbeing displaced by a nucleophile and includes halo (such as chloro,bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy(e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy),methoxy, N,O-dimethylhydroxylamino, and the like.

Compounds

In one embodiment, the present disclosure provides a compound of formula(I):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomeror a deuterated analog thereof, wherein the substituents P¹, P² and Qare as defined in this disclosure. In another embodiment of Formula (I),P¹ is H.

In another embodiment of Formula (I), P¹ is

wherein R¹, n, and m are as defined in this disclosure.

In another embodiment of Formula (I), P¹ is

wherein R¹, n, and m are as defined in this disclosure.

In another embodiment of Formula (I), P¹ is

wherein R¹, n, and m are as defined in this disclosure.

In another embodiment of Formula (I), P¹ is

The compounds of formula (I) are useful intermediates for the synthesisof various biologically active molecules, for example, compounds offormula (III):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomeror a deuterated analog thereof, wherein Z and Q are as defined in thisdisclosure.

In other embodiments of this disclosure, Q is F. In other embodiments ofthis disclosure, Z is

wherein n is 0, 1 or 2.

In other embodiments of this disclosure, Z is

In other embodiments of this disclosure, Z is

In certain embodiments of compounds of formula (I), P¹ can beselectively added or removed in the presence of the P² group. Selectivecleavage of P¹ can be accomplished by adjusting the reaction conditions,such as temperature, pH, reaction time and so forth. In someembodiments, In other embodiments of formula (I), P¹ is a pyrrolidinesulfonyl optionally substituted with 1-3 halo. In other embodiments offormula (I), P¹ is a pyrrolidine sulfonyl optionally substituted with1-3 fluoro. In other embodiments of formula (I), P¹ is a pyrrolidinesulfonyl substituted with 2 fluoro groups. In other embodiments offormula (I), P¹ is a pyrrolidine sulfonyl substituted with 1 fluorogroup. In other embodiments of formula (I), P¹ is an unsubstitutedpyrrolidine sulfonyl group.

In certain embodiments of compounds of formula (I), (Ia) or (II), P² isan amino protecting group, which is capable of forming a carbamate or anamide linkage with the amino group to which it is attached. In someembodiments, P² is an amino protecting group selected from R³—C(O)— orR⁴O—C(O)—, wherein R³ and R⁴ are each independently selected fromC₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted. In certain instances, R³ and R⁴ areeach independently selected from C₁₋₆ alkyl, aryl, heteroaryl,aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl, C₃₋₁₀cycloalkyl,C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each of which is optionallysubstituted with 1-3 R^(a) groups independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, fluoro substituted C₁₋₆alkyl,fluoro substituted C₁₋₆alkoxy, aryl, heteroaryl, C₁₋₆alkoxy, —CN, —NO₂,—OH, C₁₋₆alkyl-OC(O)—, C₁₋₆alkyl-C(O)O— or —SiMe₃, wherein the aliphaticor aromatic portion of IV is further optionally substituted with from1-3 R^(b) groups independently selected from halogen, C₁₋₆alkyl,C₁₋₆alkoxy, —CN, —NO₂ or —OH. In other instances, R³ and R⁴ are eachindependently methyl, ethyl, phenyl, 2,2,2-trichloroethyl, (CH₃)₂CHC≡C—,2-trimethylsilylethyl, 1-methyl-1-phenylethyl, cyclobutyl, cyclopropyl,allyl, vinyl, 1-adamantyl, benzyl or diphenylmethyl, each of which isoptionally substituted with from 1-3 R^(a) groups. In some embodiments,R^(a) is F, Cl, Br, I, —CH₃, Phenyl, t-butyl, MeO—, —NO₂, —CN, —CF₃,CF₃O—, —OH or —CH═CH₂. In one embodiment, P² is2,6-dichlorophenylcarbonyl. In another embodiment, P² is2,5-dichlorophenylcarbonyl, 2,3-dichlorophenylcarbonyl or2,4-dichlorophenylcarbonyl. In certain embodiments, P² is phenylcarbonyloptionally substituted with from 1-2 groups independently selected fromF, Cl, Br, CN or NO₂. In some embodiments of compounds of formula (I),P² is H, and P¹ and Q are as defined in any of the embodiments describedherein.

In some embodiments of compounds of formula (II), L¹ is Br, Cl, I,tosyl-O—, mesyl-O—, trifluoromethanesulfonyl-O—, R¹—SO₂— or R²C(O)O,wherein R¹ and R² are each independently selected from aryl,aryl-C₁₋₄alkyl or C₁₋₆alkyl, each of which is optionally substitutedwith from 1-3 R^(c) substituents selected from halogen, —CH═CH₂, —CN,—OH, —NH₂, —NO₂, —C(O)OH, —C(O)NH₂, —S(O)₂NH₂, —NHC(O)NH₂, —NHC(S)NH₂,—NHS(O)₂NH₂, —C(NH)NH₂, —OR^(d), —SR^(d), —OC(O)R^(d), —C(O)R^(d),—C(O)OR^(d), —C(S)OR^(d), —S(O)R^(d), —S(O)₂R^(d), —C(O)NHR^(d),—C(O)NR^(d)R^(d), —S(O)₂NHR^(d), —S(O)₂NR_(d)R^(d), —C(NH)NHR^(d),—C(NH)NR^(d)R^(d), —NHC(O)R^(d), —NR^(d)C(O)R^(d), —NHS(O)₂R^(d),—NR^(d)S(O)₂R^(d), —NHC(O)NHR^(d), —NHR^(d) or —NR^(d)R^(d), whereineach R^(d) is independently selected from C₁₋₆alkyl or aryl. In someinstances, R^(d) is —CH₃ , ethyl or phenyl. In some embodiments offormula (II), L¹ is Br, Cl, I, tosyl-O—, mesyl-O—,trifluoromethanesulfonyl-O—, CF₃C(O)O— or CH₃C(O)O—. In anotherembodiment of formula (II), L¹ is Br or Cl, and P² and Q are as definedin any of the embodiments described herein.

In another embodiment of formula (I), P¹ is H; and Q is F. In anotherembodiment of formula (I), P¹ and Q are H. In another embodiment offormula (I), P¹ is H; and Q is F. In another embodiment of formula (I),P¹ is H; and P² is 2,6-dichlorophenylcarbonyl. In another embodiment offormula (I), P¹ is 3-R-fluoropyrrolidine sulfonyl, 3-S-fluoropyrrolidinesulfonyl or a 3-fluoropyrrolidine sulfonyl. In yet another embodiment offormula (I), P¹ is 3-R-fluoropyrrolidine sulfonyl, P² is2,6-dichlorophenylcarbonyl, and Q is F.

Methods

Compound of formula (II) can be synthesized by those methods describedin published U.S. Publication No. 2014-0094611-A1, which is incorporatedherein by reference in its entirety. The compounds of Formula (a), (V),(VI) and (VII) can either be synthesized by those methods described inpublished U.S. U.S. Publication No. 2014-0094611-A1, or they can beobtained directly from commercial sources, or they can be obtained bymodifying commercially available starting materials using techniquesknown in the art.

In general, compound of formula (II) can be synthesized by reacting acompound of formula (a):

with an agent of the formula: P²-G under conditions sufficient to formthe compound of formula (II):

G can be selected from Br, Cl, I, tosyl-O—, mesyl-O—,trifluoromethanesulfonyl-O—, CF₃C(O)O— or CH₃C(O)O—, or the like.

In another embodiment of Formula (I), (Ia) or (II), P² is an aminoprotecting group as described in T. W. Greene and P. G. Wuts, PROTECTIVEGROUPS IN ORGANIC CHEMISTRY, (Wiley, 4th ed. 2006) or as defined in anyof the embodiments described herein, and P1 and Q are as defined in anyof the embodiments described herein.

In some embodiments, the reactions for preparing compounds of formulas(I) or (Ia) can be carried out in the presence of a base dissolved in anorganic solvent. Some preferred bases include dimethylaminopyridine(DMAP), triethylamine (TEA), N,N-diisopropylethylamine (DIPEA) andcombinations thereof. DMAP is generally present in a catalytic amount ofabout 0.05, 0.07, 0.08, 0.1, 0.2, 0.3, 0.4 or 0.5 equivalents. TEA orDIPEA can range from about 1-5 equivalents, for example, 1.0, 2.0, 3.0,4.0 or 5.0 equivalents. The organic solvents used include, but are notlimiting to, tetrahydrofuran (THF), 2-methyl-THF, acetonitrile, dioxane,dichloromethane and benzene. A preferred solvent is 2-methyl-THF. Thesolvents can be present in various volumes, e.g., 0.5, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, or 12 volumes.

Compounds of formula (a) can be prepared by contacting a compound offormula (V):

with a reducing agent under conditions sufficient to form the compoundsof formula (a). The variables, L¹ and Q are as defined in any of theembodiments described herein. In one embodiment, L¹ is Br and Q is F.The reducing agent may be, but is not limited to, tin chloride dihydrate(SnCl₂.2H₂O). Typically, 1-5 equivalents (e.g., 1, 2, 3, 4 or 5 eqs) ofthe reducing agent are used. The reaction can be carried out at atemperature of about 40-90° C., preferably about 50-70° C., morepreferably about 60° C. The solvents for the reaction can be2-methyl-THF or a mixture of 1:1 ethyl acetate/THF. The volumes of thesolvents can be from about 5 to 100 or about 7 to 80. In one embodiment,a compound of formula (V) is treated with 3 or 4 equivalents of SnCl₂ in80 volumes of 1;1 ethyl acetate/THF or 7 volumes of 2-methyl THF at 60°C.

Compounds of formula (V) can be prepared by reacting a compound offormula (VI):

with a compound of formula (VII):

in the presence of a metal halide, such as AlCl₃ under conditionssufficient to form the compounds of formula (V). X² is selected from Br,Cl, I, tosyl-O—, mesyl-O—, trifluoromethanesulfonyl-O—, CF₃C(O)O— orCH₃C(O)O—. The variables, L¹ and Q are as defined in any of theembodiments described herein. In a preferred embodiment, X² is Br or Cl.In one embodiment, Q is F, L¹ is Br and X² is Cl. The solvents used inthe reaction include, but are not limited to, CH₃NO₂, acetonitrile,dichloromethane, dioxane, dichloroethane, benzene, toluene andcombinations thereof. In one embodiment, the solvent is dichloromethane.In one embodiment, the solvent is dioxane. In another embodiment, thesolvent is 1,4-dioxane.

In another embodiment, the present disclosure provides a compound offormula (I):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomeror a deuterated analog thereof, wherein:

Q is F or H;

P¹ is,

R¹ is H or halogen;

n is 0, 1 or 2;

m is 1 or 2;

P² is —C(O)—R³ or —C(O)—OR⁴;

R³ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 R^(a) groups;

R⁴ is C ₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl,heteroaryl-C₁₋₂alkyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl,ethynyl or vinyl, each of which is optionally substituted with 1-3 R^(a)groups; and

each R^(a) group is independently halogen, C₁₋₆alkyl, fluoro substitutedC₁₋₆alkyl, fluoro substituted C₁₋₆alkoxy, aryl, heteroaryl, C₁₋₆alkoxy,—CN, —NO₂, —OH, —C(O)—O—C₁₋₆alkyl, or —SiMe₃, wherein the aliphatic oraromatic portion of R^(a) is further optionally substituted with from1-3 R^(b) groups, wherein each R^(b) group is independently halogen,C₁₋₆alkyl, C₁₋₆alkoxy, —CN, —NO₂ or —OH.

In another embodiment of the compound of formula (I), P¹ is —H. Inanother embodiment of the compound of formula (I), P¹ is pyrrolidinesulfonyl optionally substituted with 1-3 halogens. In another embodimentof the compound of formula (I), P¹ is pyrrolidine sulfonyl optionallysubstituted with 1-3 fluoro. In another embodiment of the compound offormula (I), P¹ is pyrrolidine sulfonyl optionally substituted with 1-2fluoro. In another embodiment of the compound of formula (I), P¹ ispyrrolidine sulfonyl optionally substituted with 1 fluoro. In anotherembodiment of the compound of formula (I), P¹ is 3-R-fluoropyrrolidinesulfonyl, 3-S-fluoropyrrolidine sulfonyl or a 3-fluoropyrrolidinesulfonyl. In another embodiment of the compound of formula (I), P¹ is3-R-fluoropyrrolidine sulfonyl. In another embodiment of the compound offormula (I), P¹ ethyl methyl sulfonyl.

In another embodiment of the compound of formula (I), R³ and R⁴ are eachindependently methyl, ethyl, phenyl, 2,2,2-trichloroethyl, (CH₃)₂CHC≡C—,2-trimethylsilylethyl, 1-methyl-1-phenylethyl, cyclobutyl, cyclopropyl,allyl, vinyl, 1-adamantyl, benzyl or diphenylmethyl; each of which isoptionally substituted with from 1-3 R^(a) groups, wherein each R^(a)group is independently F, Cl, Br, I, —CH₃, —OCH₃, —CH₂F, —CHF, —CF₃,phenyl, t-butyl, —NO₂, —CN, —OCF₃, —CH₃, —OCH₃, —OH or —CH═CH₂. Inanother embodiment of the compound of formula (I), R³ or R⁴ is phenyloptionally substituted with 1-2 R^(a) groups, wherein each R^(a) groupis independently F, Cl, Br, I, —CH₃, CH₂F, —CHF₂, —CF₃, t-butyl, —NO₂,—CN, —OCF₃, or —OH.

In another embodiment of the compound of formula (I), P² isphenycarbonyl optionally substituted with 1-3 halogens. In anotherembodiment of the compound of formula (I), P² is2,6-dichlorophenylcarbonyl.

In another embodiment of the compound of formula (I), P¹ is H, P² is2,6-dichlorophenylcarbonyl, and Q is F. In another embodiment of thecompound of formula (I), P¹ is 3-R-fluoropyrrolidine sulfonyl, P² is2,6-dichlorophenylcarbonyl, and Q is F.

In another embodiment, the present disclosure provides a method forpreparing a compound of formula (Ia):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomeror a deuterated analog thereof, said method comprising:

contacting a compound of formula (II):

with an agent of the formula:

under conditions sufficient to form the compound of formula (Ia),wherein:

X¹ is Sn(Bu)₃ or B(OR⁵)₂,

L¹ is Br, Cl, I, tosyl-O—, mesyl-O—, trifluoromethanesulfonyl-O—,—C(O)—O—CF₃ or —C(O)—O—CH₃C(O)O—;

Q is F or H;

P² is —C(O)—R³ or —C(O)—OR⁴;

R³ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 R^(a) groups;

R⁴ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀-cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 R^(a) groups;

R⁵ is H or C₁₋₆alkyl which can be optionally substituted with halogen,—OH, or —CN; and

each R^(a) group is independently halogen, C₁₋₆alkyl, fluoro substitutedC₁₋₆alkyl, fluoro substituted C₁₋₆alkoxy, aryl, heteroaryl, C₁₋₆alkoxy,—CN, —NO₂, —OH, —C(O)—O—C₁₋₆alkyl or —SiMe₃, wherein the aliphatic oraromatic portion of R^(a) is further optionally substituted with from1-3 R^(b) groups, wherein each R^(b) group is independently halogen,C₁₋₆alkyl, C₁₋₆alkoxy, —CN, —NO₂ or —OH.

In another embodiment of the method of preparing the compound of formula(Ia), the contacting of

with formula (II) is carried out) in 2-methyltetrahydrofuran withnitrogen.

In another embodiment of the method of preparing the compound of formula(Ia), the method further comprises adding sodium bicarbonate andbis(triphenyl)palladium(II) dichloroide.

In another embodiment of the method of preparing the compound of formula(I), the contacting of formula L²-P¹ with formula (Ia) is carried out indichloromethane and a solvent selected from the group consisting ofpyridine, dichloromethane, THF, acetonitrile, toluene, dioxane,2-methyl-THF, or a mixture thereof.

In another embodiment of the method of preparing the compound of formula(I), the contacting of formula L²-P¹ with formula (Ia) is carried out indichloromethane and pyridine.

In another embodiment of the method of preparing the compound of formula(I), the contacting of formula L²-P¹ with formula (Ia) is carried out indioxane and pyridine.

In another embodiment of the method of preparing the compound of formula(Ia), X¹ is Sn(Bu)₃.

In another embodiment of the method of preparing the compound of formula(Ia), X¹ is B(OR⁵)₂.

In another embodiment of the method of preparing the compound of formula(Ia), X¹ is B(OH)2.

In another embodiment of the method of preparing the compound of formula(Ia), L¹ is Br.

In another embodiment of the method of preparing the compound of formula(Ia), P² is 2,6-dichlorophenyl.

In another embodiment of the method of preparing the compound of formula(Ia), Q is F.

In another embodiment of the method of preparing the compound of formula(Ia), L¹ is Br, and P² is 2,6-dichlorophenyl; Q is F.

In yet another embodiment, the present disclosure provides a method forpreparing a compound of formula (I):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomeror a deuterated analog thereof, said method comprising:

contacting a compound of formula (Ia) with L²-P¹ under conditionssufficient to form the compound of formula (I), wherein:

Q is F or H;

P² is —C(O)—R³ or —C(O)—OR⁴;

P¹ is

R¹ is H or halogen;

n is 0, 1 or 2;

m is 1 or 2;

R³ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 R^(a) groups;

R⁴ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 R^(a) groups; and

each R^(a) group is independently halogen, C₁₋₆alkyl, fluoro substitutedC₁₋₆alkyl, fluoro substituted C₁₋₆alkoxy, aryl, heteroaryl, C₁₋₆alkoxy,—CN, —NO₂, —OH, —C(O)—O—C₁₋₆alkyl, or —SiMe₃, wherein the aliphatic oraromatic portion of IV is further optionally substituted with from 1-3R^(b) groups, wherein each R^(b) group is independently halogen,C₁₋₆alkyl, C₁₋₆alkoxy, —CN, —NO₂ or —OH.

In another embodiment of the method of preparing the compound of formula(I), the contacting of formula L²-P¹ with formula (Ia) is carried out inpyridine and a solvent selected from the group consisting of pyridine,dichloromethane, THF, acetonitrile, toluene, dioxane, 2-methyl-THF, or amixture thereof.

In another embodiment of the method of preparing the compound of formula(I), the contacting of formula L²-P¹ with formula (Ia) is carried out indichloromethane and pyridine.

In another embodiment of the method of preparing the compound of formula(I), the contacting of formula L²-P¹ with formula (Ia) is carried out indioxane and pyridine.

In another embodiment of the method of preparing the compound of formula(I), the contacting of formula L²-P¹ with formula (Ia) is carried out in1,4-dioxane and pyridine.

In another embodiment of the method of preparing the compound of formula(I), L¹ is Br.

In another embodiment of the method of preparing the compound of formula(I), P² is 2,6-dichlorophenyl.

In another embodiment of the method of preparing the compound of formula(I), P¹ is

In another embodiment of the method of preparing the compound of formula(I), Q is F.

In another embodiment of the method of preparing the compound of formula(I), P¹ is

In another embodiment of the method of preparing the compound of formula(I), P¹ is

In another embodiment of the method of preparing the compound of formula(I), P¹ is

In another embodiment of the method of preparing the compound of formula(I), P¹ is

In another embodiment of the method of preparing the compound of formula(I), P¹ is

In another embodiment of the method of preparing the compound of formula(I), L¹ is Br, P² is 2,6-dichlorophenyl; and Q is F.

In another embodiment of the method of preparing the compound of formula(I), L¹ is Br, P² is 2,6-dichlorophenyl; Q is F, and P¹ is

In another embodiment of the method of preparing the compound of formula(I), L¹ is Br, P² is 2,6-dichlorophenyl; Q is F, and P¹ is

In another embodiment of the method of preparing the compound of formula(I), L¹ is Br, P² is 2,6-dichlorophenyl; Q is F, and P¹ is

In another embodiment of the method of preparing the compound of formula(I), L¹ is Br, P² is 2,6-dichlorophenyl; Q is F, and P¹ is

In another embodiment of the method of preparing the compound of formula(I), L¹ is Br, P² is 2,6-dichlorophenyl; Q is F, and P¹ is

In yet another embodiment, the present disclosure provides a method forpreparing a compound of formula (III):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomeror a deuterated analog thereof, said method comprising:

(1) reacting a compound of formula (Ib):

under conditions sufficient to N-deprotect formula (I) and form thecompound of formula (III),

wherein:

Z is

R¹ is fluoro or chloro;

Q is H or fluoro;

n is 0, 1 or 2;

m is 1 or 2;

P² is —C(O)—R³ or —C(O)—OR⁴;

R³ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 substituents as described inthis disclosure; and

R⁴ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 substituents as described inthis disclosure.

In another embodiment of the method for preparing a compound of formula(III):

R³ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 R^(a) groups;

R⁴ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 R^(a) groups; and

each R^(a) group is independently halogen, C₁₋₆alkyl, fluoro substitutedC₁₋₆alkyl, fluoro substituted C₁₋₆alkoxy, aryl, heteroaryl, C₁₋₆alkoxy,—CN, —NO₂, —OH, —C(O)—O—C₁₋₆alkyl or —SiMe₃, wherein the aliphatic oraromatic portion of R^(a) is further optionally substituted with from1-3 R^(b) groups, wherein each R^(b) group is independently halogen,C₁₋₆alkyl, C₁₋₆alkoxy, —CN, —NO₂ or —OH.

In other embodiments of this disclosure, Z is

wherein n is 0, 1 or 2.

In other embodiments of this disclosure, Z is

In other embodiments of the method of preparing a compound of formula(III), the compound of formula (III) is formula (IV):

and the compound of formula (Ib) is formula (Ic):

wherein:

Q is H or fluoro;

n is 0, 1 or 2;

P² is —C(O)—R³ or —C(O)—OR⁴;

R³ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 substituents as described inthis disclosure; and

R⁴ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 substituents as described inthis disclosure.

In another embodiment of the method for preparing a compound of formula(IV):

R³ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 R^(a) groups;

R⁴ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 R^(a) groups; and

each R^(a) group is independently halogen, C₁₋₆alkyl, fluoro substitutedC₁₋₆alkyl, fluoro substituted C₁₋₆alkoxy, aryl, heteroaryl, C₁₋₆alkoxy,—CN, —NO₂, —OH, —C(O)—O—C₁₋₆alkyl or —SiMe₃, wherein the aliphatic oraromatic portion of R^(a) is further optionally substituted with from1-3 R^(b) groups, wherein each R^(b) group is independently halogen,C₁₋₆alkyl, C₁₋₆alkoxy, —CN, —NO₂, or —OH.

In another embodiment of the method of preparing the compound of formula(III) or (IIIb), formula (III) or (IIIb) is formula (IIIc):

and the compound of formula (Ib) or formula (Ic) is formula (Id):

wherein:

P² is —C(O)—R³ or —C(O)—OR⁴;

R³ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 substituents as described inthis disclosure; and

R⁴ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 substituents as described inthis disclosure.

In another embodiment of the method of preparing the compound of formula((IIIc):

R³ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 R^(a) groups;

R⁴ is C₁₋₆alkyl, aryl, heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each ofwhich is optionally substituted with 1-3 R^(a) groups; and

each R^(a) group is independently halogen, C₁₋₆alkyl, fluoro substitutedC₁₋₆alkyl, fluoro substituted C₁₋₆alkoxy, aryl, heteroaryl, C₁₋₆alkoxy,—CN, —NO₂, —OH, —C(O)—O—C₁₋₆alkyl or —SiMe₃, wherein the aliphatic oraromatic portion of R^(a) is further optionally substituted with from1-3 R^(b) groups, wherein each R^(b) group is independently halogen,C₁₋₆alkyl, C₁₋₆alkoxy, —CN, —NO₂, or —OH.

In another embodiment of the method of preparing the compound of formula(III), (IIIb) or (IIIc), R³ or R⁴ is phenyl optionally substituted with1-3 R^(a) groups, wherein each R^(a) group is independently F, Cl, Br,I, —CH₃, —CH₂F, —CHF₂, —CF₃, t-butyl, —NO₂, —CN, —OCF₃, or —OH.

In another embodiment of the method of preparing the compound of formula(III), (IIIb) or (IIIc), P² is phenycarbonyl optionally substituted with1-3 halogens.

In another embodiment of the method of preparing the compound of formula(III), (IIIb) or (IIIc), P² is 2,6-dichlorophenylcarbonyl.

In another embodiment of the method of preparing the compound of formula(III), P² is 2,6-dichlorophenylcarbonyl and Q is F.

In another embodiment of the method of preparing the compound of formula(III), the N-deprotection comprises adding ammonia in methanol.

In another embodiment of the method of preparing the compound of formula(III), formula (II) is first dissolved in tetrahydrofuran.

The agents B(OR⁵)₂ (i.e., within the definition of X¹ of

or is either commercially available or can be readily prepared inaccordance with the procedures described in the literature. In someembodiments, —B(OR⁵)₂ is:

Various palladium or nickel complexes can be used for the preparation ofcompounds of formula (III). Preferably, palladium phosphine complexesare used in the reaction. The palladium complexes include, but are notlimited to, Pd(PPh₃)₄, PdCl₂(PPh₃)₂,bis[1,2-bis(diphenylphosphino)ethane]palladium,bis(tri-t-butylphosphine)palladium,diacetobis(triphenylphosphine)palladium,tris(dibenzylideneacetone)dipalladium (Pd₂(dba)2), Pd(OAc)₂,dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II), anddichloro[1,1′-bis(di-i-propyl-phosphino)ferrocene]palladium (II). In oneembodiment, the palladium complex is PdCl₂(PPh₃)₂. The palladiumcomplexes can be present between 0.01 and 0.1 equivalents, e.g., about0.01, 0.02, 0.025, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 or 0.1equivalents. Exemplary nickel complexes include, but are not limited to,NiCl₂(dppf), bis(tricyclohexylphosphine) nickel(II) chloride (NiCl₂(PCy₃)₂) and NiCl₂(PPh₃)₂.

The Suzuki coupling reaction can be carried out in various solvents,including, but not limiting to, toluene, dioxane, THF, 2-methyl-THF,water or a mixture thereof. In one embodiment, the reaction is carriedout in dioxane or 2-methyl-THF. The reaction can be performed at atemperature between 50-100° C., 60-90° C. or 70-85° C. In oneembodiment, the reaction is carried out using 0.025-0.05 eq ofPdCl₂(PPh₃)₂, 2-3 eq of K₂CO₃ or NaHCO₃, 1 eq of compound of formula(I), 1.5-2 eq of compound of formula (IVb), 10 volumes of dioxane and 5volumes of water.

The sulfonylation reaction described herein can be carried out invarious solvents including, but not limiting to, pyridine,dichloromethane, THF, acetonitrile, toluene, dioxane, 2-methyl-THF or amixture thereof. Excess solvents can be used during the reaction, forexample, the solvents can be from 1-5 equivalents, such as 1, 1.5, 2,2.5, 3, or 4 equivalents. The temperature for the reaction can bemaintained from about 50-110° C., e.g., 50, 55, 60, 65, 70, 80, 85, 90,95, 100, 105 or 110° C. In one embodiment, the reaction is carried outin a mixed solvents of pyridine and 10 volumes of dioxane at about 100°C.

The deprotection reaction can be conducted by reacting a compound offormula (IX) with NH₃ dissolved in an organic solvent at a temperaturefrom about 50-110° C., e.g., 50, 55, 60, 65, 70, 80, 85, 90, 95, 100,105 or 110° C. The solvents used include, but are not limited to,methanol (MeOH), ethanol (EtOH), dimethylformamide (DMF),dimethylacetamide (DMA), THF, dimethylsulfoxide (DMSO), dioxane,isopropanol (IPA) or combinations thereof. In one embodiment, thereaction can be conducted at 55° C. in the presence of NH₃ (5 eq), MeOH(5 eq, 10 volumes) and DMA (5 volumes). In another embodiment, thereaction can be conducted at 100° C. in the presence of THF (5 volumes)and NH₃/IPA (12 eq).

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Certain molecules claimed in this disclosure can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are claimed.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this disclosure. Further, the compounds arecharacterized using standard methods such as mass spectroscopy, numclearmagnetic resonance (NMR) spectroscopy, etc. ¹H Nuclear magneticresonance (NMR) spectroscopy was carried out using a spectrometeroperating at 300 MHz.

Example 1 Preparation of(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,6-difluoro-3-nitrophenyl)methanone(3)

To an 50-liter flask was added 1,2-dichloroethane (DCE, 20 L), followedby 5-bromoazaindole (1) (2 kg, 10.152 mol) to result an orange slurry.Aluminum Chloride (5.421 kg, 40.608 mol) was slowly added to the flask.The first 1.5 kg of the addition was exothermic resulting a darksolution. The rest of the AlCl₃ was added to give a reaction mixture. Tothe reaction mixture was added 2,6-difluoro-3-nitrobenzoyl chloride 2(2.25 kg, 10.125 mol) via an addition funnel over a period of 1.5 h.During the addition, the reaction temperature was maintained at or below45° C. After the addition, the reaction mixture was stirred at 50° C.overnight, cooled to room temperature (˜22° C.) and transferred into twoseparate 20 L flasks. Water (25 L) and acetonitrile (12 L) were added toa 50-liter flask and cooled to 0° C. The reaction mixture was quenchedby adding water/acetonitrile solution while keeping the temperature ator below 40 ° C. The mixture obtained was filtered, and the filtrate waswashed with acetonitrile:water (1:1, 2×4 L), water (4 L) andacetonitrile (4 L), followed by drying in vacuum. Compound 3 (2.948 kg,73.4% yield) was obtained. MS (ESI): M+H⁺=382.9 and 383.9. ¹H NMR(DMSO-d₆, δ ppm): 7.55 (1 H, m), 8.47 (2 H, m), 8.53 (1 H, d, J=2.2 Hz),8.65 (1H, d, J=2.2 Hz), 13.25 (1 H, s).

Example 2 Preparation of(3-amino-2,6-difluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone(4)

A 50-liter flask was added 2-methyl-tetrahydrofuran (2-methyl-THF) (36L), compound 3 (2.85 kg, 7.455 mol) and tin(II) chloride (5.03 kg,22.365 mol). The mixture was heated to 60° C. Upon completion, thereaction was quenched with an aqueous potassium carbonate solution(20%). The resulting mixture was filtered with celite and the solidresidue was washed with 2-methyl-THF and tetrahydrofuran (THF). Thefiltrate was washed with an aqueous NaCl solution (15 L, 10%) and theorganic layer was separated. The organic layer was further washed withan aqueous NaCl solution (15 L, 20%) and concentrated on a rotovap toyield compound 4 (2.536 kg, 96.65% yield). MS (ESI): M+H⁺=353 and 354.¹H NMR (DMSO-d₆, δ ppm): 5.22 (2 H, s), 6.93 (2 H, m), 8.12 (1 H, s),8.47 (1 H, d J=2.3 Hz), 8.54 (1 H, d J−1.6 Hz), 13.2 (1 H, s).

Example 3 Preparation of(3-amino-2,6-difluoro-phenyl)-[5-bromo-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-3-yl]methanone(5)

Compound 4 (2.5 kg, 7.114 mol) obtained from Example 2 was added into a50-liter flask and cooled to 9.3° C. To compound 4 in the 50-liter flaskwas added triethylamine (0.864 kg, 8.537 mol), followed by4-dimethylaminopyridine (DMAP) (0.087 kg, 0.7114 mol) and2,6-dichlorobenzoyl chloride (1.34 kg, 6.40 mol) in 2-methyl-THF (25 L)over a period of 2 hrs. The reaction was quenched with methanol (0.30 Lat room temperature and added an aqueous NaCl solution (12.5 L, 15%) andcelite (0.5 kg). The mixture was stirred and filtered through celite.The filtrate was concentrated and added 5 volumes of heptanes. Theresulting solution was stirred for about 1 hr and dried with sodiumsulfate (1 kg) and filtered. Compound 5 was isolated by removing thesolvents under vacuum (3.47 kg, 92.93% yield). MS (ESI): M+H⁺=524,525.8, 527.8. ¹H NMR (DMSO-d₆, δ ppm): 5.36 (2 H, s), 7.01 (2 H, m),7.68 (3 H, s), 8.34 (1H, brs), 8.61 (1 H, brs), 8.72 (1 H, d J=2.3 Hz).

Example 4 Preparation of(3-(3-amino-2,6-difluorobenzoyl)-5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)(2,6-dichlorophenyl)methanone

Compound 5 (40 g, 0.076 moles) and 2-cyclopropylprimidin-5-yl-5-boronicacid (Compound A) (23 g, 0.141 moles) in 2 methyltetrahydrofuran(2-MeTHF) (1,720 mL) which 8% sodium bicarbonate (sparged with nitrogen)and bis(triphenylphosphine)palladium(II) dichloride (1 g, 0.0014 moles)were added. The mixture was heated to reflux to give Compound 6 whichwas isolated, washed and dried. (27.4 g, 64% yield). LCMS: m/z=564.0(M+H)⁺. ¹H NMR (DMSO-d6, δ ppm): 9.05 (s, 2H), 9.00 (s, 1H), 8.62 (s,1H), 8.58 (s, 1H), 7.70 (m, 3H), 7.04 (m, 2H), 5.36 (br s, 2H), 2.30 (m,1H), 1.16 (m, 4H).

Example 5 Preparation of(R)-N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide

Compound 6 (15 g, 021 moles), 1,4 dioxane (150 ml), pyridine (15 ml,49.6 moles), and Compound B (3-R-fluropyrrolidine sulfonyl chloride,11.81 g, 0.063 moles) were charged to a flask. The reaction was stirredat room temperature and then heated to 50° C. and allowed to reactovernight. Then charged to the reaction flask were ethyl acetate (60 ml)and water (60 ml). The organic layer was separated, washed, treated withactivated carbon (Darco KG-B, 2.25 g) and filtered through a celite padto yield Compound 7 (10 g, 67% yeld). ¹H NMR (DMSO-d6, δ ppm): 9.70 (s,1H), 9.02 (s, 2H), 8.81 (m,2H), 8.57 (m, 2H), 7.71 (m, 2H), 7.38 (m,2H), 5.24-5.37 (2s, 1H), 3.31-3.42 (m, 4H), 2.05-2.29 (m, 3H), 1.12 (m,4H).

Compound B was obtained by combining commercially available3-R-fluoropyrrolidine HCl salt (20 kg, 159.3 moles) and commerciallyavailable sulfuryl chloride (21 kg, 155.6 moles) in a solution ofdichloromethane (293 kg) and trimethylamine (32 kg) to yield (R)-3Fluoropyrrolidine dulfonyl chloride (Compound B, 23 kg, 77% yield).

Example 6 Preparation of(R)-N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide

Compound 7 (26.9 kg) was dissolved in tetrahydrofuran (95.8 kg) and 7Nammonia in methanol (50.2 kg) was added to the reaction mixture. Oncethe reaction was deemed complete by HPLC, Compound 8 was isolated bysolvent exchange with dichloromethane. Compound 8 was dissolved intetrahydrofuran, filtered and concentrated, and the isolated materialwas purified, isolated and triturated in WFI (Water for Injection) (17.8kg, 87% yield).

All patents, patent applications and other references cited in thespecification are indicative of the level of skill of those skilled inthe art to which the invention pertains, and are incorporated byreference in their entireties, including any tables and figures, to thesame extent as if each reference had been incorporated by reference inits entirety individually.

One skilled in the art would readily appreciate that the presentdisclosure is well adapted to obtain the ends and advantages mentioned,as well as those inherent therein. The methods, variances, andcompositions described herein as presently representative of preferredembodiments are exemplary and are not intended as limitations on thescope of the invention. Changes therein and other uses will occur tothose skilled in the art, which are encompassed within the spirit of theinvention, are defined by the scope of the claims.

While this invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention.

The disclosure illustratively described herein suitably may be practicedin the absence of any element or elements, limitation or limitationswhich is not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof” and “consisting of” may be replaced with either of the other twoterms. Thus, for an embodiment of the disclosure using one of the terms,the disclosure also includes another embodiment wherein one of theseterms is replaced with another of these terms. In each embodiment, theterms have their established meaning. Thus, for example, one embodimentmay encompass a method “comprising” a series of steps, anotherembodiment would encompass a method “consisting essentially of” the samesteps, and a third embodiment would encompass a method “consisting of”the same steps. The terms and expressions which have been employed areused as terms of description and not of limitation, and there is nointention that in the use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the disclosure claimed. Thus, it should be understood thatalthough the present disclosure has been specifically disclosed bypreferred embodiments and optional features, modification and variationof the concepts herein disclosed may be resorted to by those skilled inthe art, and that such modifications and variations are considered to bewithin the scope of this disclosure as defined by the appended claims.

In addition, where features or embodiments of the invention aredescribed in terms of Markush groups or other grouping of alternatives,those skilled in the art will recognize that the invention is alsothereby described in terms of any individual member or subgroup ofmembers of the Markush group or other group.

Also, unless indicated to the contrary, where various numerical valuesare provided for embodiments, additional embodiments are described bytaking any two different values as the endpoints of a range. Such rangesare also within the scope of the described invention.

Thus, additional embodiments are within the scope of the disclosure andwithin the following claims.

What is claimed is:
 1. A method for preparing a compound of formula (I):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomeror a deuterated analog thereof, said method comprising: contacting acompound of formula (Ia):

with L²-P¹ under conditions sufficient to form the compound of formula(I), wherein: Q is F or H; P² is —C(O)—R³ or —C(O)—OR⁴; P¹ is

R¹ is H or halogen; n is 0, 1 or 2; m is 1 or 2; R³ is C₁₋₆alkyl, aryl,heteroaryl, aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl, C₃₋₁₀cycloalkyl,C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each of which is optionallysubstituted with 1-3 R^(a) groups; R⁴ is C₁₋₆alkyl, aryl, heteroaryl,aryl-C₁₋₂alkyl, heteroaryl-C₁₋₂alkyl, C₃₋₁₀cycloalkyl,C₃₋₁₀cycloalkyl-C₁₋₂alkyl, ethynyl or vinyl, each of which is optionallysubstituted with 1-3 R^(a) groups; L² is Br, Cl, I, tosyl-O—, mesyl-O—,trifluoromethanesulfonyl-O—, —C(O)—O—CF₃ or —C(O)—O—CH₃; and each R^(a)group is independently halogen, C₁₋₆alkyl, fluoro substituted C₁₋₆alkyl,fluoro substituted C₁₋₆alkoxy, aryl, heteroaryl, C₁₋₆alkoxy, —CN, —NO₂,—OH, —C(O)—O—C₁₋₆alkyl, or —SiMe₃, wherein the aliphatic or aromaticportion of R^(a) is further optionally substituted with from 1-3 R^(b)groups, wherein each R^(b) group is independently halogen, C₁₋₆alkyl,C₁₋₆alkoxy, —CN, —NO₂ or —OH.
 2. The method of claim 1, wherein thecontacting of L²-P¹ with the compound of formula (Ia) is carried out inpyridine and a solvent selected from the group consisting of pyridine,dichloromethane, THF, acetonitrile, toluene, dioxane, 2-methyl-THF, anda mixture thereof.
 3. The method of claim 1, wherein L² is Br.
 4. Themethod of claim 3, wherein P² is —C(O)—R³ and R³ is 2,6-dichlorophenyl.5. The method of claim 4, wherein Q is F.
 6. The method of claim 5,wherein P¹ is:


7. The method of claim 1, wherein L² is Br, P² is —C(O)—R³, R³ is2,6-dichlorophenyl, Q is F, and P¹ is